A-phenylsuccinimido-halo-sulphonamido-benzenes

ABSTRACT

This invention relates to novel compounds of the formula   WHERE R1 through R7 are as hereinafter defined, of use in the treatment of Petit Mal and Grand Mal forms of epilepsy.

United States Patent 91 Pfirrmann Jan. 29,1974

[ A-PHENYLSUCCINIMIDO-HALO- SULPHONAMIDO-BENZENES [75] Inventor: Rolf Wilhelm Pfirrmann, Luceme,

Switzerland [73] Assignee: Ed Geistlich Sohne A.G. fur

Chemische Industrie, Wolhusen, Luceme, Switzerland [22] Filed: June 17, 1970 [21] Appl. No.: 47,161

[30] Foreign Application Priority Data June 18, 1969 Great Britain 30915/69 [56] References Cited FOREIGN PATENTS OR APPLICATIONS 6,614,740 4/1967 Netherlands 260/239.6

6,717,606 6/1968 Netherlands ..260/239.6

Primary Examiner-Henry R. Jiles Assistant Examiner-Cecilia U. S. Jaisle Attorney, Agent, or Firm-Bacon & Thomas 57 ABSTRACT This invention relates to novel compounds of the formula SOzNll R where R through R are as hereinafter defined, of use in the treatment of Petit Mal and Grand Mal forms of epilepsy.

4 Claims, No Drawings A-PHENYLSUCCINIMlDO-HALO- SULPHONAMlDO-BENZENES This invention relates to novel compounds of use in the treatment of epilepsy and to processes for their preparation.

The compound a-ethyl-a-methyl-succinimide has been shown to be effective against the Petit Mal form of epilepsy but it is far less effective against the Grand Mal form and its effective dose level then approaches the toxic dose level. In general, the majority of the available anti-epileptic drugs are active against either Grand Mal or Petit Mal epilepsy but not against both forms.

My copending application Ser. No. 873,741, filed Nov. 26, 1969 and now U.S. Pat. No. 3,574,194, which application is a continuation of my abandoned application Ser. No. 578,462, filed Sept. 12, 1966, and my copending application Ser. No. 692,635, now abandoned in favor of a continuation application Ser. No. 169,063, filed Aug. 4, 1971, describe succinimido benzene sulphonamides having useful anti-convulsant activity. We have now found that those having a halogenated benzene ring have shown particularly good activity and halogenated compounds have shown activity in both the electro'shock and cardiazole-shock tests, indicative of activity against both Grand and Petit Mal forms of epilepsy.

According to the present invention we provide compounds of the general formula where R, R, R and R, which may be the same or different are hydrogen atoms, aliphatic groups, cycloaliphatic groups or aryl groups or R and R or R and R may together represent a cycloalkylidene group, at least one of the substituents R, R, R and R being other than hydrogen;

R represents one or more halogen atoms; and

R and R which may be the same or different, are

hydrogen atoms, heterocyclic groups, such as pyridyl, pyrimidy] or imidazolyl groups, or aliphatic hydrocarbon groups which may, if desired, carry substituents such as x0, hydroxyl, carboxyl or esterified carboxyl, or aminoor aklylamino groups, or together with the nitrogen atom to which they are attached, form a heterocyclic group, e.g. a piperidyl or piperazyl group; and their salts with bases.

The compound l-(a-ethyl-a-methyl-succinimido)-2- chlor0-5-sulphamoylbenzene is described and claimed in my above mentioned US. Pat. No. 3,574,194 and as such is not included within the scope of the present invention.

R is either a halogen atom such as bromine, or more preferably fluorine or most advantageously chlorine. Compounds in which the sulphamoyl groups SO NR R is in the 4-position are especially preferred for their good anti-convulsant activity, especially those in which R is a chlorine or fluorine atom in the 2-position.

R and R may, for example, be alkyl groups having 1-5 carbon atoms, i.e. methyl, ethyl, propyl, butyl or amy] groups, acyl groups such as acetyl or benzoyl groups, alkoxycarbonyl groups such as ethoxy carbonyl groups, carbamyl groups e.g. the n-butylaminocarbonyl group, hydroxyalkyl groups, e.g. B-hydroxyethyl, or esterified carboxyalkyl groups e.g. ethoxycarbonylethyl groups. The preferred compounds, however, are those in which R and R are both hydrogen. The sulphonamido group is preferably in the 4-position relative to the succinimido group.

Where any of R, R R and R are aliphatic groups they are preferably alkyl or alkenyl groups, advanta geously having one to eight carbon atoms, more preferably one to five carbon atoms, for example, methyl, ethyl, propyl, butyl, amyl, hexyl, heptyl or allyl groups, which may carry substituents such as aryl groups, for example phenyl groups, which may be substituted as described below. Such groups may thus include benzyl, phenethyl and phenylallyl groups one or more of R, R, R and R may be a cycloaliphatic group, for example a cycloalkyl or cycloalkenyl or two adjacent groups, i.e. R and R or R and R, may constitute together a cycloalkylidine group such as a cyclopentylidene or cyclohexylidene group. Cycloalkyl groups may, for example, include cyclopentyl and cyclohexyl groups while cycloalkenyl groups may, for example, include cyclopentenyl and cyclohexenyl groups in which the double bond is in any of the available positions. Such groups in general preferably contain three to eight carbon atoms, advantageously four to seven carbon atoms.

Where one or more of R, R R and R is aryl, or ar aliphatic, this may carry one or more alkoxy, methylene dioxy, nitro, cyano, acyl, carboxyl, esterified carboxyl, amino, alkylamino, sulphonamido or acylamido groups or halogen atoms. The phenyl or chlorophenyl group is preferred.

The substituents R and R may advantageously be a methyl group and a hydrogen atom or ethyl or phenyl group respectively while R and R are preferably both hydrogen atoms; R is also advantageously a phenyl group while R, R and R are hydrogen atoms.

The new compounds form salts with bases, for example alkali metal salts e.g. sodium salts or salts with ammonia or amines.

The compound l-(a-ethyl-a-methyl-succinimido)-2- chloro-4-sulphamoyl-benzene has shown especially favourable properties in our pharmacological tests as compared with l-(a-ethyl-a-methyl-succinimido)-4- sulphamoylbezene, which is the best compound disclosed in our said earlier cases. The peroral LD of both compounds is of the order of 4000 mg/kg or greater in mice as compared with a-ethyl-a-methylsuccinimide which has a peroral LD in mice of about 1500 mg/kg. In the electro-shock test, which is indicative of action against Grand Mal epilepsy, the peroral ED of l-(a-ethyl-a-methyl-succinimido)-2-chloro-4- sulphamoylbenzene in mice was as low as 10 mg/kg while in albino rats the corresponding value was 5-10 mg/kg as compared with 5 mg/kg and 25 mg/kg respectively for the non-chlorinated sulphonamide. a-Ethyl-a-methyl-succinimide shows an ED in the same tests of 500 mg/kg. In the cardiazol shock test, which is indicative of effectiveness against Petit Mal epilepsy, the peroral ED of l-(a-ethyl-amethylsuccinimido )-2-chloro-4-sulphamoyl-benzene was shown to be 50 mg/kg., as against 600 mg/kg for the unchlorinated sulphonamide and 200 300 mg/kg. for a-ethyl-a-methyl-succinimide; it will also be noted that 3 4 the ratio of ED ILD is significantly better for the benzene compound according to the invention. This compound l-(a-hexyl-succinimido)-2-chloro-4-sulphamoylshowed no sedative activity up to 500 mg/kg. benzene Table 1 below illustrates the pharmacological results l-(a-heptylsuccinimido)-2-chloro-4-sulphamoyl obtained in our experiments in respect of a number of 5 benzene further compounds according to the invention. 1-( i i id 2- hl 4 l h l Antiepileptic Effect ED Toxicity:

Compound of LD Electro shock. Cardiazol Shock. Example No, Mice Mice RHS R815 I2 l0 200 7000 5 2.5-l 100 16 7000 5 50 benzene l-(a-methyl-a'phenyl-succinimido )-2-chloro-4- sulphamoyl benzene,

Other compounds according to the invention have sim- 3O ilar properties; the particularly preferred products include:

l-(a-methylsuccinimido )-2-chloro-4-sulphamoyl l'(a'methyl'a'phenyl'succmlmldo benzene, sulphamoyl benzene,

l-(a-methyl-succinimido )-2-chloro-5-su1phamoyl 3 5 1 y "P y banzeney sulphamoyl benzene 1-(a-methyl-succinimido)-5-chloro-2-sulpham0yl 'p y P Y benzene, benzene l-(a-methyl-succinimido)-2-fluoro-4-sulphamoyl l-(a-methyl-a-phenyl-succimimido)-3-chloro-4-sulbenzene, 40 phamoyl-benzene l-( a-methyl-a-succinimido )-2-fluoro-5-sulphamoyl l-(a-methyl-oz-phenyl-succinimido )-2-chloro-5-sulbenzene, phamoyl-benzene fl-methyl-a-ethyl'Succinimido l-( a-methyl-a-phenyl-succinimido )-2-fluoro-4-( N- sulphamoyl benzene acetyl-sulphamoyl)-benzene 1 y y 4 5 1-(a-methyl-a-phenylsuccinimido )-2-fluoro-4-( N- P mQY f i fia a H ethyl-sulphamoyl)-benzene a-methyl-a-ethyl-succinimido l-( a-phenyl-succinimido )-2-chloro-4-sulphamoyl sulphamoyl benzene, benzene 1-( y y l-(a-phenyl-succinimido )-2-fluoro-4-sulphamoyl sulphamoyl benzene, 50 benzene y y 1-(a-phenyl-succinimido)-3-fiuoro-4-sulphamoyl sulphamoyl benzene, benzene y y l -(a-phenyl-succinimido )-2-fluoro-4-(N-ethylsulethyl-sulphamoyl)-benzene, phamoyl)-benzene l-(a-cyclohexl -enyl-succinimido )-2-chloro-4-sul- 5 5 l-(a-phenyl-succinimido )-2-chloro-4-( N- phamoyl-benzene ethylcarboxyl-sulphamoyl)-benzene l-(a-cyclohexyl-succinimido)-2-chloro-4-sulphaml-(a-phenyl-succinimido )-3 ,5 -dichloro-4-sulphamoyl-benzene oyl-benzene l-(a,a-cyclohexylidene-succinimido)2-chloro-4- l (a-phenylsuccinimido)-2-chloro-4-(N-acetylsulsulphamoyl benzene, phamoyl)-benzene l-( a-cyclohex-2-enyl-succinimid0 )-2-chloro-4-sul- 1-(a-phenyl-succinimido-3-chloro-4-sulphamoylphamoyl-benzene benzene.

l-(a-cyclopent-2-enyl-succinimido)-2-chloro-4-sul- According to a further feature of the invention we phamoyl-venzene provide pharmaceutical compositions containing one l-(a-cyclopentyl-succinimido)-2-chloro-4-sulphamor more compounds according to the invention tooyl-benzene gether with one or more pharmaceutical carriers or exl-(a-pentylsuccinimido)-2-chloro-4-sulphamoylcipients.

Thus, for example, the compositions may take the form of tablets, coated tablets, capsules, lozenges, suppositories, ampoules for injection, solutions, etc.

The carriers or excipients in such compositions may, for example be those conventional for such forms and may include starch, lactose, magnesium stearate, talc, gelatin, sterile pyrogen-free water, or suspending, emulsifying, dispersing, thickening or flavouring is reacted with a succinic acid derivative of the general formula HOOC CRR CR R" COOH ill or a reactive derivative thereof such as anhydride or a monoor diester, e.g. a lower alkyl ester, preferably having one to five carbon atoms, for example a methyl or ethyl ester, where R, R R R R, R and R have the meanings given above, to form the desired succinimido derivative.

The reaction with the free succinic acid, anhydride or ester may be effected in a single stage, or in two stages. In the latter case, the initial product will have the general formula (or its isomer in which the hemisuccinyl group is attached by the carbonyl adjacent to the groups R and R) and may be isolated, if desired, before final cyclisation. In general the final condensation requires a reaction temperature of the order of 200C and for single stage condensations the reaction is preferably carried out between 100 and 200C. The half-condensation of the succinic acid of formula IV generally takes place within the range 80 100C.

Similarly, the initial condensation to form the product of formula IV is readily effected by merely heating in an inert solvent, e.g. a hydrocarbon, nitrohydrocarbon, chloro-hydrocarbon, ether or cyclic ether solvent. The second stage to effect cyclisation may be effected, for example, in the presence of a dehydrating agent such as an anhydrous salt, e.g. sodium acetate, or sulphuric, phosphoric or polyphosphoric acid or phosphorus pentoxide or simply by heating in the temperature range 200C in the absence of a solvent with or without a vacuum.

The reaction time for the reaction with the free acid is preferably one to five hours, advantageously about 2 hours. The one-stage reaction with the anhydride is preferably effected at about 200C for a short time.

The sulphonamido compounds according to the invention may also be prepared from corresponding compounds laclting a sulphonamido group by reaction with reagents for introducing a sulphonamido group. Thus, for example, a compound of formula I in which R represents an aryl or araliphatic group having no sulphonamido group may be reacted with a sulphonyl halide, to form a halosulphonyl derivative which may then be reacted with ammonia or an amine of the formula Nib-R 11 where R and R have the above meanings. It is also possible to introduce an amino group by nitration or by using a nitroaniline in the initial succinimide condensation and to convert this to sulphonyl halide by reduction, diazotisation and treatment with sulphur dioxide in the presence of cuprous halide. Alternatively, a halogenated succinimide-aminobenzene may be prepared by the reaction of the corresponding halogenated aminobenzene derivative with the acid of formula III or a reactive derivative thereof; if necessary the amino group may be protected before reaction.

The compounds of formula I in which one or both of R and R are hydrogen can be used to prepare derivatives thereof. Thus, for example, acylation gives the acyl derivatives e.g. by reaction with an acyl halide or anhydride; alkylation gives the alkyl derivatives, e.g. by reaction with an alkyl halide, sulphate, sulphonate etc. Hydroxylalkylation gives the hydroxyalkyl derivative, e.g. by reaction with ethylene oxide; carbamylation gives the corresponding urethane, e.g. by reaction with a carbonyl dihalide followed by reaction with ammonia or an amine. Urethane derivatives can be prepared, for example, by reaction with a haloformic acid ester, e.g. a chloroformic acid ester, preferably an alkyl ester having one to five carbon atoms in the alkyl group. Saturated substituents R R R or R can be prepared from corresponding unsaturated substituents and thus, for example, an n-propyl substituent can be prepared from an allyl substituent or a cycloalkyl substituent from a cycloalkenyl substituent by reduction, e.g. catalytic hydrogenation, for example using a platinium catalyst.

In order that the invention may be well understood we give the following Examples by way of illustration only (all temperatures are in C )1 Example 1 l-( a-Methylsuccinimido-2-chloro-4- sulphamoyl benzene 3-Chloro-4-aminobenzene sulphonamide (2.0 g) and a-methyl-succinic acid (1.3 g) were heated together in an oil bath at until no further water vapour was given off. The mixture was then cooled, taken up in ethyl acetate, precipitated with a little ether and petroleum ether and allowed to stand a short while. The precipitate was then collected to yield 2.1 g pale beige crystals, m.p. 148155. On recrystallisation from ethyl acetate/petroleum ether (charcoaled), white crystals were obtained, m.p. l75-l76 C l-l N O SCl requires C 43.68; H 3.66, N 9.27, Cl 11.72; found C 43.98, H 3.80, N 9.12, Cl 11.94%. Example 2 1(a-Methylsuccinimido)-2-chloro-5-sulphamoyl-benzene 1-(a-Methylsuccinimido)-2-chlorobenzene (28.4 g) was added with stirring to chlorosulphonic acid (140 ml). The mixture was then heated at 150 for 15 minutes, cooled and added dropwise to ice. The precipitated brown product was collected and dissolved in chloroform to give a deep yellow solution which was dried. Ammonia gas was then introduced. The precipitate was removed and the chloroform solution evaporated to give a viscous oil (16.7 g). The oil was dissolved in ethyl acetate, filtered over charcoal and mixed with petroleum ether. The pale yellow crystals formed, m.p. 176178, were recrystallised from ethyl acetate petroluem ether to give m.p. 178l80. Example 3 1-( a-Methyl-a-ethyl-succinimido)-2- bromo-S-sulphamoyl benzene l-( a-Methyl-a-e thyl-succinimido )-2-bromobenzene (5.0 g) was added with stirring to chlorosulphonic acid (25 ml) and the mixture heated to 120C for 15 minutes. The mixture was then cooled, added dropwise to ice (250 g) and the preceipitated product collected. The product was dissolved in chloroform (50 ml) and the solution added dropwise with stirring to concen trated aqueous ammonia (50 ml) and the mixture refluxed for 20 minutes. The mixture was then cooled and evaporated to dryness in vacuo. The residue was stirred with ethyl acetate and water and the ethyl acetate phase evaporated dried and evaporated to give a brown oil (3.2 g). This oil was dissolved in ethyl acetate, filtered over charcoal, and the filtrate mixed with petroleum ether and cooled. The separated product was collected as white crystals m.p. 176-178 C. C H N O SBr requires C 41.60; H 4.03, N 7.47; found C 41.54, 1+ 4.11, N 7.4%. Example 4 1-(a-Methyl-ethylsuccinimido)-2-fluoro-5- sulphamoyl benzene l-(a-Methyl-a-ethyl succinimido)-2-fluorobenzene (10.0 g) and chlorosulphonic acid (50 ml) were mixed with stirring and heated briefly to 140 and then for minutes at 120. The mixture was then cooled and added dropwise to ice/water and the precipitated product collected. The crude product was dissolved in chloroform and added dropwise to concentrated aqueous ammonia (50 ml). The mixture was stirred at 50 for minutes, cooled and evaporated in vacuo. The residue was taken up in ethyl acetate and water and the ethyl acetate phase separated and shaken with 1N sodium bicarbonate and with 2N hydrochloric acid. The ethyl acetate phase was then dried, charcoaled, concentrated, mixed with petroleum ether and allowed to stand. The precipitated beige crystals, m.p. 110-l15 were recrystallised from ether/petroleum ether and dried in vacuo to give white crystals m.p. l57l58. C, -,H N O SF requires C 49.72, H 4.82, N 8.92; C 49.6, H 4.91, N 8.94%. Example 5 1-(a-Methyl-a-ethyl-succinimido)-2- chloro-4-sulphamoyl benzene a-Methyl-a-ethylsuccinic anhydride (15.0 g) and 3-chloro-4-aminobenzene sulphonamide (7.5 g) were heated together to an oil bath at 170-l 80 for 90 minutes, then at 220 for 30 minutes. The melt was cooled, dissolved in ethyl acetate and shaken with 1N sodium bicarbonate and with 2N hydrochloric acid. The ethyl acetate phase was then dried, charcoaled and mixed with petroleum ether. The mixture on cooling precipitated white crystals (10.0 g) m.p. 175-176. C H, N O SCl requires C 47.24, H 4.58, N 8.47; found C 47.28, H 4.39, N 8.61%. Example 6 l-(a-Methyl-a-phenylsuccinimido )-2- fluoro-4-sulphamoyl benzene 3-Fluoro-4-aminobenzenesulphonamide (1.9 g.) and a-methyl-a-phenylsuccinic anhydride (1.9 g.) were heated together for 1 hour at 190C. The resulting mixture was cooled, dissolved in ethyl acetate and shaken with 2N hydrochloric acid and then with 1N sodium bicarbonate. The ethyl acetate solution was dried, filtered over charcoal and the filtrate evaporated to dryness to give a cloudy oil (3.0 g.). This oil was dissolved in ether, petroleum ether added and the precipitate collected as white crystals of m.p. C. These were recrystallised from methanol/water to give white crystals, m.p. 150 152C.

C H, N O SF requires C 56.40, H 4.18, N 7.74; C H N O SF found C 56.30, H 4.26, N 7.79% Example 7 1-(a-Methyl-a-ethylsuccinimido)-2-fluoro- 4-sulphamoyl benzene 3-Fluoro-4-aminobenzenesulfonamide (9.4 g.) and a-methyl-a-ethylsuccinic anhydride (7.0 g.) were heated together at to C for 15 minutes. The cooled mixture was dissolved in ethyl acetate and the solution shaken with 2N hydrochloric acid and then with 1N sodium bicarbonate. The solution was dried, evaporated to dryness and the residue treated with petroleum ether to yield light beige crystals 7.5 g. m.p. 139144C). Recrystallisation from ethylacetate/petroleum ether gave white crystals (m.p. 142-144C).

C, -,H,,,N O.,SF requires C 49.72, H 4.82, N 8.92

C H N O SF found C 49.97, H 4.85, N 9.42%.

Example 8 1-a-Methylsuccinimido-5-chloro-2- sulphamoyl benzene 2-Amino-4-chlorobenzenesulphonamide (2.0 g.) and a-methylsuccinic acid (1.3 g.) were heated together at 150C for 2 hours. The reaction mixture was cooled and dissolved in ethyl acetate. The solution was washed with 2N hydrochloric acid and with 1N sodium bicarbonate, dried and evaporated down to yield a brown oil (2.1 g.) which was dissolved in ether, filtered over charcoal and left to stand overnight. The precipitate was collected as white crystals (m.p. 176 182C) Recrystallisation from ethyl acetate/petroleum ether gave white crystals (m.p. 184/ 188C).

C H N O SCl requires C 43.68, H 3.66, N 9.27, C1

1 1.72 C H ,N O SC1 found C 43.54, H 3.76, N 9.39, Cl

Example 9 1-(a-Methyl-a-ethylsuccinimido)-5-chloro- Z-sulphamoylbenzene 2-Amino-4-chlorobenzene sulphonamide (10.3 g.) and a-methyl-a-ethyl-succinic anhydride (7.1 g.) were heated together at 190C. The mixture was cooled and dissolved in ethyl acetate and shaken with 2N hydrochloric acid and with 1N sodium bicarbonate, dried and filtered over charcoal. The filtrate was mixed with petroleum ether and the precipitate collected as white crystals (6.5 g. m.p. l90200C). Recrystallisation from ethylacetate/petroleum ether gave white crystals m.p. 198201C. C H N O SCI requires C 47.17, H 4.57, N 8.46, Cl 10.71; found C 47.10, H 4.61, N 8.50, C] 10.82%

9 Example l-(a-Methyl-a-phenylsuccinimido)-2- chloro-4-sulphamoyl-benzene 3-Chloro-4-aminobenzene sulphonamide (2.0 g.) and a-methyl-a-phenyl succinic anhydride (2.4 g.) were heated together at 210C for 20 minutes. The cooled mixture was then dissolved in ethyl acetate and shaken with 2N hydrochloric acid and with lN sodium bicarbonate. The solution was dried and evaporated down to yield a pale yellow cloudy oil (3.0 g.) which was dissolved in ethyl acetate, filtered over charcoal and the filtrate mixed with petroleum ether. The precipitate was collected as white crystals (m.p. 120130C). The crystals were boiled with 2N hydrochloric acid and the insoluble matter collected and dried to give white crystals (m.p. 144-l46C) C,-,H,,,N,O.,SC1 requires C 53.87, H 3.99, N 7.39;

found C 53.80, H 4.07, N 7.44%. Example 1 1 l-(a-Methyl-a-phenylsuccinimido)-2- bromo-4-sulphamoyl benzene 3-Bromo-4-anilino benzene sulphonamide (1.25 g.) and a-methyl-a-phenylsuccinic anhydride (0.95 g.) were heated together at 190C. for 1 hour. The cooled mixture was then dissolved in ethyl acetate, and the solution shaken with 1N sodium bicarbonate and with 2N hydrochloric acid, dried and evaporated down. The residue, a brown oil (2.0 g.), was dissolved in ethyl acetate and charcoal filtered. The filtrate was mixed with petroleum ether, cooled and the precipitate collected as white crystals (m.p. l50-l54C).

C,,H, N O SBr requires C 48.27, H 3.57, N 6.62;

found C 48.06, H 3.54, N 6.91% Example 12 l-(a-Phenylsuccinimido)-2-bromo-4-sulphamoyl-benzene 2.5 g of 3-bromo-4-aminobenzene-sulphonamide and 1.9 g of phenylsuccinic acid are heated together to 190C and held at this temperature for minutes. After cooling the mixture is taken up in ethyl acetate and extracted with 1N HCl and NaHCO The ethyl acetate solution is dried with Na SO filtered and evaporated to yield 3.8 g of beige crystals which are dissolved in acetone, filtered over charcoal mixed with petroleum ether and cooled and the precipitate suction filtered. 1.5 g of white crystals, m.p. 203205C Recrystallised with acetone/petroleum ether, m.p. 206-208C Analysis Calc. C 46.98%; H 3.20%; N 6.85%; Found C 47.27%; H 3.29%; N 6.60%. Example 13 1-(a-Phenylsuccinimido)-2-chloro-5-sulphamoyl-benzene 5.5 g of 3-amino-4-chlorobenzene-sulphonamide and 5.2 g of phenylsuccinic acid are heated together for 1 hour at 208C. The mixture is subsequently dissolved in ethyl acetate and extracted with 2N HCl and 1N NaHCO The ethyl acetate solution is dried with Na- SO and filtered over charcoal. The filtrate is somewhat concentrated, mixed with petroleum ether, cooled and the precipitate suction filtered 6.2 g of white crystals, melting point 186-188C. Recrystallized with ethyl acetate/petroleum ether; white crystals, m.p. l86-187C Analysis Calc. C 52.72%; H 3.59%; N 7.69%; Found C 53.05%; H 3.87%; N 7.40%; Example 14 l-( a-Methyl-a-ethylsuccinimido)-2- bromo-4-sulphamoylbenzene 2.5 g of 3-bromo-4-aminobenzene sulphonamide and 1.4 g of a-methyl-a-ethylsuccinic anhydride are heated together at 185C and subsequently held at C. After cooling it is dissolved in ethyl acetate and extracted with 2N HCl and 1N NaHCO The ethyl acetate is dried, filtered over charcoal and evaporated. 0.8 g of yellow oil is taken up in acetone, mixed with petroleum ether, cooled and the precipitate suction filtered. Beige crystals, m.p. 170-174C. Recrystallised with acetone/ether-petroleum ether, white crystals, m.p. 173-175C. Analysis Calc. C 41.63%; H 4.03%; N 7.47%; Found C Example 15 l-(a-Phenylsuccinimido)-2-chloro-4sulphamoyl-benzene 2.0 g of 3-chloro-4-aminobenzene sulphonamide and 1.9 g of phenylsuccinic acid were heated together to 220C, held for 30 minutes at this temperature and then dissolved in ethyl acetate extracted with 2N HCl and 1N NaHCO the ethyl acetate solution being dried with Na SO filtered and then evaporated, the residue finally being mixed with ethyl acetate and the insolubles suction filtered.

1.4 g of white crystals m.p. 202205C Recrystallised with methanol/ether-petroleum ether;

white crystals. m.p. 205207C Analysis Calc. C 52.65%; H 3.59%; N 7.68%; Found C 52.59%; H 3.73%; N 7.61%. Example 16 l-(a-Phenylsuccinimido)-2-fluoro-4-sulphamoyl-benzene I 1.9 g of 3-fluoro-4-aminobenzene sulphonamide and 2.0 g of phenylsuccinic acid are heated together for 1 hour at 160C. After cooling, the mixture is dissolved in ethyl acetate and extracted with 2N HCl and 1N NaHCO The ethyl acetate solution is dried over Na, 80,, filtered over charocal, concentrated somewhat, mixed with petroleum ether, cooled and the precipitate suction filtered. 1.6 g of white crystals, m.p. l77178C, recrystallised with ethyl acetate; white crystals, m.p. l77178C Analysis Calc. C 55.22%; H 3.77%; N 8.05%; Found C 55.30%; H 3.83%; N 7.80%. Example 1 7 1-(a-Methylsuccinimido)-2-fluoro-4-sulphamoyl-benzene 1.9 g of 3-fluoro-4-aminobenzene sulphonamide and 1.4 g of methylsuccinic acid are heated together for 1 hour at 160C. After cooling the melt is dissolved in ethyl acetate and extracted with 2N HCl and 1N NaH- C0 The ethyl acetate solution is dried with Na SO filtered over charcoal, somewhat concentrated and the residue mixed with petroleum ether, cooled and the precipitate suction filtered. 1.3 g of white crystals, m.p.: (168) l76-l77C Recrystallised with ethyl acetate/petroleum ether, white crystals, m.p. 176177C. Analysis Calc. C 46.19%; H 3.88%; N 9.80%; Found C Example 18 1-(a-Methylsuccinimido)-2-bromo-4-sulphamoyl-benzene 2.5 g of 3-br0mo-4-arninobenzene sulphonamide and 1.3 g of methylsuccinic acid are heated together at 180C and then held for 15 minutes at this temperature. The brown oil is then taken up in ethyl acetate and extracted with 2N HCl and 1N NaHCO The ethyl acetate solution is dried with Na SO filtered over charcoal, mixed with petroleum ether and the precipitate suction filtered 1.8 g of beige crystals, m.p. 193-197C Recrystallised with acetone/petroleum ether, white crystals. m.p. 20320SC Analysis Calc. C 38.07%; H 3.2%; N 8.07%; Found. C

Example 19 1-(a-Phenylsuccinimido)-2-fluoro-4-(N- ethylsulphamoyl)-benzene a. l-amino-2-fluorobenzene-4-sulphonic ethylamide i. l-acetylamino-2-fluorobenzene-4-sulphonic acid chloride is added dropwise with stirring to excess ethylamine. The reaction solution is evaporated, the product taken up in ethyl acetate, washed with 2N HCl and the ethyl acetate solution evaporated again. Colourless crystals, m.p. 158160C ii. By saponifying with 20% HCl, boiling under reflux, neutralising with NaOH and filtering off the precipitate, a 70% yield of 1amino-2-fluorobenzene-sulphonic acid-N-ethylamide is obtained; m.p. 8083C.

b. 9.5 g of phenylsuccinic acid 10.0g l-amino-2- fluorobenzene-4-sulphonic acid-N-ethylamide are heated together in a large boiling vessel for hour at 220C. After cooling the reaction mixture is dissolved in ethyl acetate and subsequently extracted successively with 2N HCl, 1N sodium bicarbonate solution and water. The ethyl acetate solution is subsequently dried over sodium sulphate and evaporated.

Yield 15.4 g of light yellow oil. The mixture is again dis solved in ethyl acetate, filtered over activated carbon and again evaporated. The same process is repeated. Yield, almost white, solidified foam which did not crystallise. A sample was sent for analysis Calc. C 57.49%; H 4.56%; N 7.45%; Found. C

Example 20 1-(a-Phenylsuccinimido)-2-chloro-4-(N- ethoxy-carbonylsulphamoyl)-benzene 3.6 g of 3-chloro-4-(a-phenylsuccinimido)-benzene sulphonamide and 36.30 g of potassium carbonate are suspended in 300 ml of acetone and subsequently 1.4 g of ethyl chloroformate is added. The mixture is refluxed for 15 hours, during which the suspension becomes slightly pink. After cooling, the inorganic salts are suction filtered and washed with a little acetone and the mother liquor is evaporated.

Yield: 5 g of slightly pink crystals, very readily soluble in water; this is the potassium salt. The slightly pink crystals are dissolved in a little water, precipitated again with 2N HCl and suction filtered. The substance is then dissolved in ethyl acetate, dried over sodium sulphate and evaporated again.

Yield: 4.6 g of semicrystalline mass which is dissolved in methylene chloride, filtered over activated charcoal, and evaporated to dryness. This purification step was then repeated.

Yield: 1.6 g of colourless crystals, m.p. 78-84C. A sample is again filtered over methylene chloride, evaporated and well dried. Despatched for analysis.

acid-N- Calc. C 52.28%; H 3.39%; N 6.42%; found. C

52.69%; H 4.14%; N 6.00%. Example 21 l-(a-Cyclohex-en-l-yl-succinimido)-2- chloro-4-sulphamoyl-benzene (probably associated with some 1-(a,a-cyclohexylidenesuccinimido)-2- chloro-4-sulphamoyl-benzene) 5.0 g of 2-(cyclohex-en-1-yl)-mono-ethylsuccinate and 4.8 g of 2-chlorosulphani1amide are heated together for 7 hours in a N atmosphere, taken up in 200 ml of ethyl acetate and extracted as follows: (20 ml each) 3 times with 2N HCl, once with water, 3 times with 1N NaHCO once with water, and once with brine. The brine is then back extracted once with ml of ethyl acetate. The combined ethyl acetate phases are subsequently dried over Na SO filtered and evaporated. The brown-yellow residue is repeatedly extracted with hot methylene chloride accompanied by shaking. The insoluble product is discarded and the methylene chloride solution filtered through charcoal and evaporated. The 5.0 g of brown resin is shown by thin layer chromatography still to contain a trace of the starting material and is thus taken up in 150 ml of ethyl acetate/hexane 2:1 and extracted as follows: (20 ml each) 6 times with 5 N HCl, once with water, and once with brine. It is dried over Na SO filtered and evaporated to yield 2.7 g of yellow solidified foam. Sample for analysis:

Calc: C 52.09%; H 4.64%; Cl 9.62%; N 7.59%;

Found: C 52.05%; H 4.75%; Cl 9.79%; N 7.57%. Example 22 1-(a-Phenylsuccinimido)-3,5-dichloro-4- sulphamoyl-benzene 12.0 g of 3,S-dichlorosulphanilamide and 9.6 g of phenyl succinic acid are intimately mixed and held for 8 hours in the autoclave at 220C under N After cooling, the mixture is dissolved in chloroform/ether 1:3 and extracted as follows: 5N HCl, 6 times with 40 ml; water, once with 50 ml; 1N NaHCO;,, 5 times with 50 ml; brine, once with 50 ml. The brine is then back extracted once with 300 ml of chloroform/ether. The combined organic phases are dried over Na SO filtered, evaporated in vacuo to yield 11.6 g of brown resin. It is chromatographed on 330 g of silica gel, using chloroform/ether 1:2 as the eluant: 1st fraction 500 ml of dark brown resin discarded 2nd fraction 1000 ml of yellow resin 3rd fraction 1000 ml of violet oil discarded The 2nd fraction was decolourised by means of activated charcoal and from crystallised ethyl acetatehexane to yield 1.1 g; m.p. l64-170C. Recrystallisation from ethyl acetate hexane for analysis gave 09 g; m.p. 180182C Calc. C 48.18%; H 3.03%; Cl 17.79; N 7.02%;

Found. C 48.09%; H 3.10%; Cl 17.61%; N 7.18%.

Example 23 l-(a-Pentylsuccinimido)-2-chloro-4-sulphamoyl-benzene 1.6 g of pentylsuccinic acid and 1.7 g of 2-chloro-4- sulphonamidoaniline are heated together for 40 minutes at 200C. The cooled dark brown solid product is dissolved in ether and extracted with 2N HCl and 1N NaHCO The ethereal solution is subsequently washed with water, filtered over activated charcoal, dried over sodium sulphate and evaporated Yield 1.4 g of light yellow oil. Recrystallisation once from ether petroleum ether Yields 0.95 g of almost white crystals, m.p. l32134C. Subsequent recrystallisation five times from ether petroleum ether gives crystals of m.p.

13 135l 39C Sample of this substance sent for analysis.

Calc. C 50.25%; H 5.34%; N 7.85%; Found. C

Example 24 1(a-Heptylsuccinimido)-2-chloro-4-sulphamoyl-benzene 10.0 g of heptylsuccinic acid and 10.5 g of 2-ch1oro- 4-sulphonamidoanilihe heated at 170C until no more water vapour distils off. The reaction mixture is then dissolved in 300 ml of ethyl acetate and extracted twice with 100 ml each of 2N HCl, 1N NaHCO and water. The ethyl acetate solution is dried over sodium sulphate, filtered over activated charcoal and evaporated. Yield 14.8 g of light yellow oil, which is dissolved in 300 ml of ether and again filtered over activated charcoal. The ethereal solution is mixed with petroleum ether and crystallisation is induced by scratching with a glass rod to yield 4.2 g of a white substance of m.p. 122-125C. Subsequent recrystallisation 3 times from ether-petroleum ether yields 2.2 g of snow white crystals; m.p. l24-127C. A sample thereof sent for analy- Calc. C 52.83%; H 6.00%; N 7.25%; Found. C

Example 25 1-(a-Phenylsuccinimido)-2-chloro-4-N- acetyl-sulphamoyl-benzene 7.3 g of 3-chloro-4-(a-phenyl-succinimido)-benzenesulphonamide, 3.2 g of pyridine and 35 ml of acetic anhydride are refluxed together for 2% hours and subsequently evaporated in vacuo to yield 10.9 g of brown grease which is dissolved in ethyl acetate and extracted with 2N HCl and water. The ethyl acetate solution is dried over sodium sulphate and subsequently evaporated to yield 8.1 g of light beige solidified foam; m.p. 103-l C. A sample is recrystallised 3 times from water. A small quantity of the yield is sent for analysis; m.p. 1l0-115C Calc. C 53.18%; H 4.46%; N 6.83%; Found. C

Example 26 1-(a-n-Hexylsuccinimido)-2-chloro-4-sulphamoyl-benzene 2.0 g of n-hexylsuccinic acid and 2.0 g of 3-chlorosulphanilamide are heatedtogether in a boiling vessel via an oil bath, until no more water vapour can be distilled off. After cooling a brown grease remains which is dissolved in 100 ml of ethyl acetate and extracted twice each with 50 ml each of NaHCO solution, 2N HCl and water. The ethyl acetate solution is subsequently filtered hot over activated carbon and dried over sodium sulphate. After distilling off the ethyl acetate the remaining oil has a yellowish colour. Dissolution in ether takes place, followed by filtering over activated carbon. The solution is 50 percent concentrated and accompanied by cooling in the CO bath and the addition of petroleum ether the oil is crystallised. Yield 0.5 g of snow white crystals; m.p. 126-130C. Then recrystallised twice from ether in petroleum ether; m.p. l32-l35C.

Calc. C 51.57%; H 5.70%; N 7.52%; Found. C

Example 27 1-(a-Phenylsuccinimido)-3-fluoro-4-sulphamoyl-benzene 5.0 g of 2-fluoro-4-aminosulphonamide and 5.1 g of phenylsuccinic acid are heated together for 3 hours at 190C. The mixture is taken up in ethyl acetate and washed 3 times with 2N l-lCl, once with water, 3 times with 1N NaHCO once with water, then subsequently extracted once with ethyl acetate, dried over Na SO evaporated and crystallised from ethyl acetateether. Yield 7.0 g m.p. 194-198C Recrystallised from ethyl l-198C Calc. C 55.13%; H 3.76%; N 8.04%; Found. C

54.89%; H 3.88%; N 8.11%. Example 28 1-(wCyclohex-2-enylsuccinimido)-2- chloro-4sulphamoyl benzene 5.4 g of cyclohex-Z-enylsuccinic anhydride and 6.2 g of 3-chloro-4-aminobenzene sulphonamide are heated together to 200C. After cooling the mixture is dissolved in ethyl acetate and extracted with 2N HCl and 1N NaHCO dried and evaporated. Yield 9.5 g of brown oil, which is dissolved in ethyl acetate, filtered over charcoal, mixed with petroleum ether, cooled and suction filtered to yield white crystals of m.p. 147-150C. Recrystallised with ether/petroleum ether to yield white crystals; m.p. 151-153C. Analysis Calc. C 52.08%; H 4.64%; N 7.59%; Found C 52.15%; H 4.68%; N 7.66%. Example 29 1-(a-Cyclopent-2-enylsuccinimido)-2'- chloro-4-su1phamoyl benzene 5.0 g of cyclopent-2-enyl-succinic anhydride and 6.2 g of 3-chloro-4-aminobenzene sulphonamide are heated together at 240C. After cooling the mixture is taken up in ethyl acetate, extracted with 2N HCl and 1N NaHCO dried and evaporated. Yield 7.5 g of brown foam product which is chromatographed in ethyl acetate on g of neutral aluminium oxide in ethyl acetate; the ethyl acetate is evaporated. Yield: a white foam product which cannot be crystallised A sample was sent for analysis Calc. C 50.75%; H 4.26%; N 7.89%; Found. C

50.78%; H 4.35%; N 7.94%. Example 30 1-(a-Methylsuccinimido)-3-fluoro-4-sulphamoyl-benzene acetate-ether, m.p.

4.0 g of 2fluoro-4-aminobenzene sulphonamide and 4.0 g of 2-methyl-2-phenylsuccinic anhydride are heated together for 3 hours at C, taken up in ethyl acetate and washed three times with 2N HCl, once with water, three times with 1N NaHCO and again once with water, then subsequently extracted once with ethyl acetate, dried over Na SO evaporated and crystallised from ethyl acetate hexane (filtered through charcoal).

Yield s.o"g-, m.p. 178-181C Recrystallised from ethyl acetate hexane; m.p. l82-184C 2. By catalytic hydrogenation of 2-chloro-4- nitrobenzene sulphonamide in alcohol with palladium charcoal the 2-chloro-4-aminobenzene sulphonamide is obtained in 85% yield which crystallises from alchohol/water; m.p. 174176C.

b. 6.0 g of 2-chloro-4-aminobenzene sulphonamide and 5.7 g of phenylsuccinic acid are heated together for 2 hours at 190C, taken up in ethyl acetate, washed three times with 2N HCl, once with water, three times with 1N NaHCO and once with water, back-extracted once with ethyl acetate, dried over Na SO evaporated and crystallised from ethyl acetate-ether-hexane (filtered through charcoal).

Yield 1.8 g; m.p. 1982l4C.

Boiled in ml of methanol, well cooled and suction filtered Recrystallised from methanol; m.p. 21 1214C Calc. C 52.68%; H 3.59%; N 7.69%; Found. C

Example 32 1-(a-Cyclopentylsuccinimido)-2-chloro-4- sulphamoyl benzene 3.5 g of (cyclopenten-Z-yl)-succinimide-2-chloro-4- sulphonamide benzene are dissolved in 50 ml of methanol and 0.1 g of PtO is added thereto. Hydrogenation duration 15 minutes: in theory 290 ml of H in practice 280 ml. The catalyst is removed and the solvent evaporated. The residue is a foam product which cannot be crystallised. Sample of the foam is supplied for analysis.

Analysis Calc. C 50.46%; H 4.80%; N 7.85%; Found. C

Example 33 1-(a-Allylsuccinimido)-2-chloro-4-sulphamoyl-benzene 5.6 g of allylsuccinic anhydride and 8.3 g of 3-chl0ro- 4-aminobenzene sulphonamide are heated together to 200C, kept at this temperature for 45 minutes, taken up in ethyl acetate, extracted with 2N HCl and 1N NaHCO dried with ethyl acetate and evaporated. Yield 10.6 g of brown oil, which is dissolved in a large volume of ether, filtered, concentrated to 250 ml, cooled and the precipitate suction filtered to give white crystals; m.p. 141-146C. It is then recrystallised several times with ethyl acetate/petroleum ether over charcoal to give white crystals; m.p. 147l49C Analysis Calc. C 47.46%; H 3.98%; N 8.52%; Found C Example 34 1-(a-Methyl-a-phenylsuccinimido)-2- fluoro-4-(N-ethylsulphamoyl)-benzene 2.18 g of 3-fluoro-4-aminobenzene sulphonic acid ethylamide and 1.90 g of a-methyl-a-phenylsuccinic anhydride are heated together to 210C, then dissolved in ethyl acetate and extracted with 2N HCl and 1N NaHCO dried and evaporated. Yield 1.65 g of brown oil which is dissolved in ethyl acetate, filtered over charcoal and evaporated to yield a colourless resin. Analysis Calc. C 58.51%; H 4.91%; N 7.18%; Found. C

Example 35 1-(a-Methyl-a-phenylsuccinimido)-3- ch1oro-4-sulphamoyl benzene 5.5 g of 2-chloro-4-aminobenzene sulphonamide and 5.2 g of 3-methyl-3-phenylsuccinic anhydride are mixed and heated to 190C, cooled after 3 hours and taken up in ethyl acetate. The solution is washed 3 times with 2N HCl, once with water, 3 times lN NaH- CO once with water, twice with brine and back extracted once with ethyl acetate, dried over Na SO and evaporated to yield 8.8 g of dark brown oil. It is crystallised from ethyl acetate hexane to give 3.8 g; m.p. l96-202C and recrystallised from ethyl acetate hexane; m.p. 198-202C Analysis Calc. C 53.94%; H 4.00%; N 7.40%; Found. C

Example 36 l-(a-Methyl-a-phenylsuccinimido)-2- chloro-S-sulphamoyl benzene 1.0 g of 3-amino-4-chlorobenzene sulphonamide and 0.95 g of a-phenyl-a-methylsuccinic anhydride are heated together to 210C, then dissolved in ethyl acetate, extracted with 2N HCl and 1N NaHCO dried with ethyl acetate, filtered over charcoal, crystallised with ether/petroleum ether, cooled and the precipitate suction filtered. Yield 1.0 g of white crystals; m.p. 1 10C which are recrystallised with acetone/etherpetroleum ether to yield white crystals; m.p. 9395C.

Analysis Calc. ,C 53.87%; H 3.99%; N 7.39%;

Example 37 1-(a-Methyl-a-phenylsuccinimido)-2- fluoro-4-(N-acetyl-sulphamoyl)-benzene 3.6 g of 3-fluoro-4-(a-methyl-a-phenylsuccinimide)-4-sulphamoyl-benzene and 1.6 g of pyridine (2 mol) are refluxed for 2 hours with 15 ml of acetic anhydride, and evaporated in vacuo. The brown oil is taken up in ethyl acetate, extracted with 2N HCl, dried and chromatographed neutral over 60 g neutral alumina. The ethyl acetate solutions are then concentrated somewhat and filtered over charcoal, crystallised with the addition of ether/petroleum ether and suction filtered to yield white crystals; m.p. 134-136C, then recrystallised again with ethyl acetate/ether-petroleum ether to yield white crystals; m.p. 135136C Analysis Calc. C 56.48%; H 4.74%; N 6.93%; Found. C

Example 3 8 l-( a-Metnyl-oz-ethylsuccinimido 3- fluoro-4-sulphamoyl benzene 3.7 g of a-methyl-a-ethylsuccinic anhydride and 4.9 g of 2-fluoro-4-aminobenzene sulphonamide are heated together for 90 minutes at l90C, then taken up in ethyl acetate, extracted with 2N HCl and 1N NaHCO dried and evaporated. The residue is crystallised from acetone/petroleum ether to yield 4.3 .g of white crystals; m.p. l34l40C and then recrystallised from acetone/petroleum ether to yield white crystals; m.p. 141-143C Analysis Found. C

Calc. C 49.72%; H 4.82%; N 8.92%; Found. C.

49.70%; H 4.97%; N 8.56%. Example 39 1-(a-Methyl-a-ethylsuccinimido)-3- chloro-4-sulphamoyl-benzene 4.3 g of 2-chloro-4-aminobenzene sulphonamide and 3.0 g of 3-methyl-3-ethylsuccinic anhydride are mixed and heated for 1% hours at 200C, cooled and taken up in ethyl acetate, washed three times with 2N HCl, once with water, three times with 1N NaHCO once again with water, twice with brine, back-extracted once with ethyl acetate, dried over Na SO and evaporated to yield 6.95 g of brown oil which is filtered through charcoal in ethyl acetate-hexane and crystallised to yield 4.7 g; m.p. l34-l40C, recrystallised from ethyl acetate-hexane to yield 4.3 g; m.p. 154-164C. Recrystallised from ethyl acetate-hexane; m.p. 154164C. Analysis Calc. C 47.19%; H 4.57%; N 8.47%; Found C Example 40 l-(oz-Methyl-a-ethylsuccinimido)-2- fluoro-4-(N-ethylsulphamoyl)-benzene 2.18 g of 3-fluoro-4-aminobenzene sulphonic acid ethyl amide and 1.42 g of a-methyl-a-ethylsuccinic anhydride are heated together to 210C, kept at this temperature for 30 minutes, taken up in ethyl acetate, extracted with 2N HCl and 1N NaHCO dried and evaporated to yield 3.3 g of brown oil. This is mixed with 50 ml of water, refluxed for 30 minutes and extracted with ether, the ether solution being washed with 1N NaH- CO dried and evaporated to yield a yellow oil which can be crystallised with ether/petroleum ether to yield white crystals; m.p. l02104C Analysis Calc. C 52.68%; H 5.60%; N 8.19%; Found. C

Example 41 l-(a-Cyclohexylsuccinimido)-2-chloro-4- sulphamoyl-benzene 2. 8 g of (cyclohexen-2-yl)-succinimide-2- chlorobenzene-4-sulphonamide are dissolved in 50 ml of methanol, 0.1 g of Pt0 is added thereto and hydrogen passed in for 10 minutes, the uptake being in theory ml of H in practice ml. The catalyst is then removed, the solvent evaporated, the residue dissolved in ether and precipitated with petroleum ether and the preceipitate suction filtered to yield white crystals of m.p. l59l70C.

These are dissolved in tetrahydrofuran-ether, filtered over charcoal, mixed with petroleum ether and the precipitate suction filtered to yield white crystals, m.p.-

fluoro-4-sulphamoyl-benzene. 

2. The compound 1-( Alpha -phenyl-succinimido)-2-chloro-4-sulphamoyl-benzene.
 3. The compound 1-( Alpha -phenyl-succinimido)-2-sulphamoyl-benzene.
 4. The compound 1-( Alpha -phenyl-succinimido)-3-fluoro-4-sulphamoyl-benzene. 